Serotonin (or 5-hydroxytryptamine) is a monoamine transmitter produced in the raphe nuclei in the brainstem, exerting widespread influence in the CNS. Serotonergic pathways have long been known to be involved in modulating acute and chronic pain, anxiety and depression, diverse and complex effects that are mediated by a range of receptor subtypes (Bardin, 2011; Yam et al., 2018; Heijmans et al., 2021; Hao et al., 2023). The central actions of this monoamine can be either inhibitory (analgesia) or excitatory (hyperalgesia), and it has pro-inflammatory effects in the periphery. For example, serotonergic neurons project inferiorly from the raphe nuclei to the segmental dorsal horn, with either facilitatory or inhibitory effects on local neurons (Bear et al., 2016). These projections are a component of the endogenous diffuse noxious inhibitory control (DNIC) system. The DNIC system is a functional grouping of hypothalamic and ponto-medullary neurons (the PAG, raphe nuclei and locus coeruleus) that modulate signaling at spinal levels and are themselves subject to influence from forebrain and limbic regions, and autonomic and somatosensory systems. DNIC operates through opioid peptides and nor-adrenaline as well as serotonin (Baldry and Thompson, 2005). The end-result is prolonged altered activity in primary and projection neurons within the dorsal and anterolateral tracts (Zain and Bonin, 2019; Pereira-Silva et al., 2023). Notable too are the systemic central influences of serotonergic raphe neurons projecting rostrally to higher centers (Bear et al., 2016).

Noradrenaline is a catecholamine produced in several small brainstem nuclei in the pons and medulla. Descending projections from the locus coeruleus (A6) and perhaps A5 are noradrenergic contributions to DNIC, with antinociceptive effects (e.g., Kucharczyk et al., 2023). However, typical of the complex phenomenae of pain and responses to injury, peripheral noradrenaline has little impact in pain-free individuals yet there is evidence for both anti and pro-nociceptive effects in injured or inflamed tissues (Pertovaara, 2013). Moreover, circulating nor-adrenaline (and adrenaline) is critical to the hormonal stress response, with distributed effects contributing to other tangible aspects of the experience of pain or music; notably, respiratory and cardiac dynamics, blood pressure, and metabolism (Bear et al., 2016).

As with serotonin, the dopaminergic system is a widely distributed network with potential influence on pain perception. Dopaminergic neurons from the substantia nigra, ventral tegmental area, and subthalamic nuclei modulate functions involving prefrontal and cingulate cortices, the basal ganglia, NAc, thalamus, hippocampus and brainstem (Figure 1, Bear et al., 2016). Learning, reward and movement execution are major implications from cortical dopaminergic transmission. Subcortically, dopamine influences PAG function that, together with opioid signaling, contributes to descending modulation of nociception, outcomes that vary depending on the type of dopamine receptor that is involved (Li et al., 2019; Kummer et al., 2020; Cabon et al., 2021; Neugebauer et al., 2023). There are direct projections from the (hypothalamic) A11 nucleus to the spinal trigeminal nucleus in the brainstem and dorsal horn of the spinal cord, with likely modulatory effects on nociception (Charbit et al., 2009; Li et al., 2019). Chronic pain experiences are associated with significant changes in functional connectivity, including evidence of altered dopamine signaling in for example striatum, PFC and NAc (Jaaskelainen et al., 2001; Li et al., 2019; Kummer et al., 2020; Zhang et al., 2022). Leknes and Tracey (2008) cite observations linking altered dopamine related activity with changes in pain perception and the experience of pleasure, likely via interactions with opioids (see below). Indeed, they argue that: “These two neurotransmitter systems are thus likely to mediate the brain’s common currency, allowing for action selection based on the comparison between competing pleasant and aversive events” (Leknes and Tracey, 2008, p. 318).

The body makes its own opioid peptides (e.g., β-endorphin, enkephalins, and dynorphin) that bind to different opioid receptors. β-endorphin signals through μ-opioid receptors, enkephalins bind to both μ-and δ-receptors, the latter with higher affinity, and dynorphin binds to κ-receptors. The μ-and δ-opioid receptors have similar functions but in regions such as ACC, PFC, amygdala and NAc the κ-opioid receptor can have an opposing influence, and there is also interaction with dopaminergic circuits (Neugebauer et al., 2023). Many studies have focused on β-endorphin and the distribution of μ-opioid receptors. β-endorphin is produced mostly in hypothalamic and pituitary cells, and released into the bloodstream from the pituitary gland as well as influencing many regions within the CNS. In the brain the μ-opioid receptor is widely distributed and found in high density in ACC, PFC, OFC, insula, NAc and somatosensory cortex, as well as in the amygdala, hippocampus, diencephalon, PAG, locus coeruleus, RVM and spinal cord (Figure 1). In humans, μ-opioid receptor availability is generally slightly higher on the right hand side of the brain, with the exception of NAc and amygdala, where a left sided bias is seen (Kantonen et al., 2020). Note that peripheral levels of β-endorphin do not necessarily predict how a given individual responds to pain or opioid analgesia (Leonard et al., 1993; Bruehl et al., 2017), perhaps related to inter-individual variability of μ-opioid receptor levels as well as age-related changes in receptor availability (Kantonen et al., 2020).

Opioid medicines are widely used to treat pain but have substantial issues (Deyo et al., 2015; de Sola et al., 2020). Because opioid receptors are distributed throughout the CNS and periphery, notably the gastrointestinal tract, these medicines have multiple adverse effects (e.g., constipation), lose effectiveness with prolonged use and are potentially addictive (Deyo et al., 2015; Cashin et al., 2023). In some instances there is development of increased pain - a secondary condition termed opioid-induced hyperalgesia (Higginbotham et al., 2022). In addition, as noted earlier, opioids can influence the activity of other receptor types including dopamine, serotonin, oxytocin, glutamate and GABA – influences that are often reciprocal. Clinical examples of these interactions include the opioid medicines tramadol (serotonergic and noradrenergic [Grond and Sablotzki, 2004]) and tapentadol (noradrenergic, weakly serotonergic [Singh et al., 2013]). As a result, opioids can influence not only nociception at a number of levels but also many other psychophysiological and cognitive functions including learning and memory, reward, social interactions, mood and stress (Pilozzi et al., 2021; Putnam and Chang, 2022; Neugebauer et al., 2023). For all of these reasons, considerable effort is directed towards reducing opioid usage, an outcome that – as discussed later - can result from the use of music-based interventions in pain management.

In human positron emission tomography (PET) studies, use of radioactive ligands has revealed alterations in the binding potential of μ-opioid receptors in chronic pain sufferers (e.g., Zubieta et al., 2001; Maarrawi et al., 2007; Li Y.- J. et al., 2023; Li Z. et al., 2023). Depending on the type of chronic pain under examination, a decrease in μ-opioid receptor binding has been described in OFC, PFC, ACC, NAc, striatum, ventral tegmental area (VTA), PAG, insula and medial thalamus. This is generally interpreted as an indication of increased receptor occupancy and therefore greater release and presence of endogenous opioids. However, it is possible that these changes may also reflect an altered affinity of a particular ligand for μ-opioid receptors and/or receptor down regulation (Niikura et al., 2010). Importantly, combined with the release from axons there is more distant and distributed volume transmission of β-endorphin in the CSF and brain, broadening and extending its influence on function (Veening et al., 2012).

In the periphery, β-endorphin tends to reduce immune responses, however opioids can also reduce physiological responses to stress, and have anti-inflammatory actions (Pilozzi et al., 2021). In this context, peripheral opioid expression levels are altered in chronic pain states and have been reported to be inversely related to the degree of perceived pain (Brejchova et al., 2021). In addition, there is ex vivo evidence that all three opioid receptors are expressed by circulating immune cells (macrophages, monocytes, lymphocytes and granulocytes) themselves, and when stimulated these cells can release opioid peptides (β-endorphin, met-enkephalin and dynorphin) that act on receptors expressed in DRG and trigeminal ganglion neurons, resulting in reduced nociceptive transmission (Sun et al., 2019; Machelska and Celik, 2020; Brejchova et al., 2021).

In the brain this nine amino-acid peptide is synthesized in several circumscribed regions within the hypothalamus. It is released into the bloodstream from the posterior pituitary but oxytocin expressing neurons also send axons to numerous parts of the CNS. Brain regions showing overlap of oxytocin receptors with areas activated by music that is familiar, rewarding, arousing and/or motivating are summarized in Figure 1 (Quintana et al., 2019; Harvey, 2020). Oxytocin has a remarkably wide range of actions both peripherally and centrally. It is perhaps best known for its role before and after childbirth, stimulating the uterus and lactation. It is also important in attachment and bonding, and together with the opioids is linked to many aspects of human social behavior including cooperativity, trust and emotional empathy (Harvey, 2020; Putnam and Chang, 2022). The peptide also has beneficial systemic effects on the cardiovascular and immune/inflammatory systems, and the regulation of appetite and glucose homeostasis (e.g., Li et al., 2017; Lawson et al., 2019; Onaka and Takayanagi, 2019; Reiss et al., 2019; Jankowski et al., 2020; Niu et al., 2021; Liu et al., 2022; Nishimura et al., 2022). The immune regulatory and anti-inflammatory effects may have an impact on pain perception, although in humans there is evidence for altered oxytocin levels in some chronic pain conditions (Goodin et al., 2015; Mekhael et al., 2023). Importantly, oxytocin is now well established to act centrally, both in the spinal cord and brain, to reduce the perception of pain (Yang et al., 2022). These anti-nociceptive actions may be mediated by the oxytocin receptor itself or via interaction with opioid and other neuromodulator systems, but in addition the peptide has calming and anxiolytic effects (Kirsch et al., 2005; Neumann and Slattery, 2016; Herpertz et al., 2019), is often negatively correlated with cortisol, and can reduce stress (Lee et al., 2015; Schladt et al., 2017; Neumann and Landgraf, 2019). In some circumstances oxytocin may act to reduce memory of adverse or fearful events (e.g., Donadon et al., 2018; Hu et al., 2019; Giovanna et al., 2020; Baldi et al., 2021), all important in the affective, psychophysiological response to acute and chronic pain (Boll et al., 2018).

The physiological actions of oxytocin are mediated by its own receptor, but oxytocin is also a positive allosteric modulator of μ-and κ-opioid receptors, enhancing signalling when studied in vitro (Meguro et al., 2018; Miyano et al., 2021). Consistent with this, oxytocin induced analgesia after injection of the peptide into rat PAG or NAc is blocked by μ-κ- but not δ-opioid receptor blockers (Ge et al., 2002; Gu and Yu, 2007). As discussed earlier, the oxytocin receptor also forms functional complexes with dopamine and serotonin receptors. At the synaptic and pathway level, the actions of oxytocin released from the hypothalamus can interact with and modulate other neurotransmitter systems including dopamine (Li et al., 2020), serotonin (Yoshida et al., 2009; Borroto-Escuela et al., 2022), glutamate, GABA (e.g., Breton et al., 2008; Nishimura et al., 2022), and the important nociceptive receptor transient receptor potential vanilloid 1 (TRPV1) (Nersesyan et al., 2017; Sun et al., 2018; Biurrun Manresa et al., 2021; Shuba, 2021).

In animal studies, analgesic effects of oxytocin have been described after experimentally induced acute (Rash et al., 2014), neuropathic and inflammatory pain experiences (Yu et al., 2003; Condes-Lara et al., 2005; Eliava et al., 2016; Sun et al., 2018; Hilfiger et al., 2020; Li et al., 2021; Esmaeilou et al., 2022; Nishimura et al., 2022; Iwasaki et al., 2023; Krabichler and Reynders, 2023; Li Y.- J. et al., 2023; Li Z. et al., 2023), and increased expression of oxytocin receptors has been reported after chemotherapy-induced neuropathic pain in mice (Li et al., 2023a). Similar to the distribution of oxytocin receptors in the CNS (Insel and Shapiro, 1992; Quintana et al., 2019) the anatomical location of these oxytocinergic effects is widespread, although in mice at least, there is not always congruence between oxytocin output and receptor expression (Son et al., 2022). Thus, while preclinical rat studies have shown that the analgesic effects of oxytocin can be blocked by both oxytocin receptor and sometimes μ-opioid receptor antagonists (e.g., Ge et al., 2002; Miranda-Cardenas et al., 2006; Gu and Yu, 2007), as with β-endorphin, release of oxytocin beyond synaptic sites into the extracellular space and even into the CSF suggests more widespread indirect effects of the peptide, significantly extending its potential modulatory influence and functional range (Chini et al., 2017; Son et al., 2022).

With regard to nociception, oxytocin influences physiological activity in known pain-related sites in the brain such as PAG, prefrontal and somatosensory cortex, ACC, insula, amygdala, NAc, raphe and hypothalamus (Figure 1) (e.g., Gu and Yu, 2007; Eliava et al., 2016; Boll et al., 2018; Poisbeau et al., 2018; Li et al., 2021; Saito et al., 2021; Nishimura et al., 2022; Yang et al., 2022; Iwasaki et al., 2023; Li et al., 2023a). Receptors are also found in the spinal cord and on a proportion of peripheral sensory neurons in the dorsal root ganglia (DRG) (Condes-Lara et al., 2005; Gong et al., 2015; González-Hernández et al., 2017; Poisbeau et al., 2018; Martinez-Lorenzana et al., 2021; Noguri et al., 2022; Yang et al., 2022; Li Y.- J. et al., 2023; Li Z. et al., 2023). Evidence from transgenic rat studies has also been presented suggesting effective analgesic action via both neuronal and humoral pathways (Nishimura et al., 2022). In this experimental model, oxytocin reduced pro-inflammatory mast cell degranulation and, under certain pathological conditions, induced anti-inflammatory effects that were mediated via the hypothalamic/pituitary/adrenal axis. Central analgesia involved activation of neurons in locus coeruleus and dorsal raphe. In turn there was altered inhibition in the dorsal horn which could be specifically blocked using an oxytocin receptor antagonist (Nishimura et al., 2022).

The autonomic nervous system (ANS) regulates the internal physiological environment, including blood pressure, heart rate, digestion, and respiration. It also has a critical role in sexual arousal. CNS influences arise from various regions in the brainstem as well as the limbic system and hypothalamus (Ellis and Thayer, 2010). There are three components – the sympathetic, parasympathetic and enteric nervous systems. Put simply, the sympathetic and parasympathetic nervous systems work together in a homeostatic fashion, often with opposing outcomes. The former tends to drive activity (“fight or flight” response), increase heart rate and blood pressure etc., while the latter acts to reduce heart rate and blood pressure, and increase more rest-related activities such as digestion. Importantly, mental or physical stress is associated with greater sympathetic activity, a serious health risk if long-term stress is not controlled.

A useful measure of sympathetic/parasympathetic balance is heart rate variability (HRV). Lack of variability is associated with stress, anxiety and/or chronic pain, and has been linked to dysregulated parasympathetic activity (Ellis and Thayer, 2010; Tracy et al., 2016; Ginsberg et al., 2022). Although some heterogeneity is evident, analysis of music-related studies that have measured HRV as well respiratory rate and other cardiovascular signs show that music-based interventions increase HRV and can – dependent to some extent on the type of music that is presented (Davis and Thaut, 1989; Knight and Rickard, 2001; Ooishi et al., 2017) - lower heart rate and blood pressure, all indicative of increased vagal tone and enhanced activity in the parasympathetic nervous system (Okada et al., 2009; Koelsch and Jäncke, 2015; Wang et al., 2020; Ginsberg et al., 2022; Metzner et al., 2022; Ting et al., 2022; Cao and Zhang, 2023; Park et al., 2023). These signs of re-balancing of the ANS are often associated with reduced pain perception and often accompanied by a reduction in the stress related hormone cortisol (McKinney, Antoni, et al., 1997a; Grape et al., 2003; Kreutz et al., 2004; Koelsch et al., 2011, 2016; Ooishi et al., 2017; Fu et al., 2019). Reduced plasma levels of adrenaline and nor-adrenaline have also been reported (Okada et al., 2009). While not directly linked to peripheral nociceptive processing, these indications of reduced sympathetic activity and stress are linked to changes in activity in frontal and prefrontal cortex and are important when considering the impact that anxiety can have, increasing the perception of chronic pain (Du et al., 2022).

Inflammatory and immunomodulatory changes contribute to the development of, and prolong the experience of, chronic pain (Ronchetti et al., 2017; Sawicki et al., 2021; Seidel et al., 2022). Peripheral inflammation or tissue injury involves an increased presence of mast cells, lymphocytes, monocytes and macrophages, with greater levels of pro-inflammatory agents such as IL-6 and IL-1β, tumor necrosis factor (TNF) α, bradykinin, prostaglandin-2, serotonin histamines, tachykinins, substance P, and interferon-γ (Luchting et al., 2015; Ronchetti et al., 2017; Yam et al., 2018; Seidel et al., 2022). These agents promote inflammation and healing (in early stages), alter (“sensitize”) response profiles of sensory afferents and feature in systemic processes subserved by the HPA axis. Throughout the CNS, glial cell activity changes, particularly microglia and astrocytes (Sawicki et al., 2021; Chen Y. L. et al., 2022; Chen W. G. et al., 2022), potentially affect the efficacy of opioids (Pahan and Xie, 2023) and alter synaptic dynamics.

With regard to music, its analgesic and immuno-homeostatic effects have been linked to several neuromodulatory systems (Fancourt et al., 2014). For example:

Reduced sensitivity to pain after communal music making has been interpreted as an indication of increased endorphin expression (Dunbar et al., 2012; Tarr et al., 2015; Weinstein et al., 2016). Consistent with this, the opioid antagonist naltrexone blocked the decrease in pain sensitivity reported after synchronous dancing (Tarr et al., 2017). These are interesting observations, however the perception of pain may not always reflect circulating levels of β-endorphin (Bruehl et al., 2017; Ahn et al., 2019), and there is inconsistency in music-induced changes in plasma levels of factors related to β-endorphin activity (McKinney et al., 1997b; Stefano et al., 2004). Increased serum (Grape et al., 2003; Nilsson, 2009; Keeler et al., 2015) or salivary (Kreutz, 2014; Yuhi et al., 2017) levels of oxytocin have been reported after singing or group drumming, as well as when listening to relaxing music (Ooishi et al., 2017). These effects can be moderated by social context, mood and level of empathy (Schladt et al., 2017; Eerola et al., 2021; Bowling et al., 2022), changes in the functionality of these systems in various chronic pain states (Bruehl et al., 2012; Ahn et al., 2019; Brejchova et al., 2021; Mekhael et al., 2023), and opioid-oxytocin and opioid-immune interactions (Meguro et al., 2018; Miyano et al., 2021; Pilozzi et al., 2021).

Nociceptors are primary afferents that respond to thermal (heat or cold, burns), mechanical (tissue injury, pressure) or chemical stimuli (ischaemia, inflammation) through a variety of receptors. Response profiles are often higher than other afferents, meaning these neurons transduce stimuli more likely to be threatening or noxious (hence, nociceptors). Nociceptors comprise myelinated Aσ-fibers and unmyelinated C fibers, both of which synapse in select laminae of the dorsal horn or in brainstem nuclei. Their cell bodies are located in the DRG or spinal trigeminal ganglia (Bear et al., 2016).

Phenotypic and functional changes in nociceptors are associated with nascent and persistent pain experiences; often involved in inflammation and immune dysregulation (Esposito et al., 2019). It is possible some aspect of music-induced analgesia may be mediated at this level, principally because nociceptor sub-populations express receptors for β-endorphin, oxytocin, nor-adrenaline and/or serotonin (Gold et al., 1997; Matsushita et al., 2018; Martinello et al., 2022; Noguri et al., 2022). As noted immediately above, music reduces nor-adrenaline, increases oxytocin and has variable effects on serotonin. It is also possible the alterations in the immuno-inflammatory cascade promoted by music positively influence response profiles of nociceptive afferents, given the increased responsiveness of these cells is partly driven by pro-inflammatory signaling.

The spinal cord is a major site of nociceptive modulation, involving many neuroactive agents and mediated by complex synaptic interactions between afferent sensory inputs and descending and local excitatory and inhibitory circuits. The functional output from this milieu is further complicated by altered activity and signaling across pain conditions, and by individual differences in response profiles (e.g., D’Mello and Dickenson, 2008; Heijmans et al., 2021; Koning et al., 2023). Recent studies also implicate astrocytes in modulatory mechanisms within spinal cord (Chen Y. L. et al., 2022; Chen W. G. et al., 2022). Overall, in persistent pain conditions there is generally increased ascending nociceptive activity and reduced descending anti-nociceptive influence, the literature not always in agreement as to the extent to which this sensitization is peripheral or central in origin – or perhaps a variable combination of both (e.g., Cheng et al., 2015; Tracy et al., 2015; Bannister, 2019; Brazenor et al., 2022; Mendell, 2022; Treede, 2022; Adams et al., 2023).

Musical modulation of nociceptive transmission at the spinal cord level, potentially involving β-endorphin, oxytocin, dopamine, nor-adrenaline and/or serotonin, has been demonstrated. Listening to favorite music affected neural responses not only in cortex and brainstem but also in the dorsal gray of the spinal cord, interpreted as being due to descending influences originating in the PAG (Dobek et al., 2014). Similarly, the nociceptive spinal reflex, skin conductance and pain perception were reduced after listening to pleasant (but not arousing) music (Roy et al. (2012)). Several recent studies have assessed the effect of music on TSP and CPM/DNIC. While one study did not observe changes in either pain sensitivity mechanism when healthy subjects listened to favorite music (Colebaugh et al., 2023), two other studies reported that TSP but not CPM/DNIC was significantly reduced when listening to music of some kind (Chai et al., 2020; Cabon et al., 2021).

The foregoing discussion has provided evidence that at least some of the known antinociceptive impact of music results from physiological effects mediated in the periphery and at spinal and brainstem levels, involving both ascending and descending systems, and likely involving a variable combination of β-endorphin, oxytocin, dopamine, nor-adrenaline and/or serotonin interactions. The potential complexity already evident becomes even greater when considering how exposure to and/or involvement in music influences higher emotional and cognitive processes, and the extent to which these processes influence the overall subjective, multidimensional experience of acute and chronic pain, including descending influence on TSP and DNIC (Dobek et al., 2014; Garza-Villareal et al., 2017; Powers et al., 2022). Elucidating the connectional architecture and underlying mechanisms that directly link music to pain perception at higher levels is not easy because additional contextual influences such as valence, distraction, meditation, fear, anticipation and expectation come into play (e.g., Lunde et al., 2019; McCarberg and Peppin, 2019; Gamal-Eltrabily et al., 2021; Tan and Kuner, 2021; Brazenor et al., 2022; Lunde et al., 2022; Powers et al., 2022; Adams et al., 2023).

As described earlier, in music-based interventions that target subjective pain relief, music is most effective if it is chosen by the person with pain and combines elements that are familiar, pleasant, rewarding and/or anxiolytic. The more focus, engagement, and cognitive agency (Howlin and Rooney, 2021; Howlin et al., 2022, 2023) the person has, the better. Social context also appears to be important (Linnemann et al., 2016). The higher order regions involved in these aspects of a musical experience include the amygdala, ACC, insula, the caudate nucleus and NAc, superior temporal gyrus, somatosensory cortex, and orbitofrontal, ventromedial, dorsomedial and dorsolateral prefrontal cortices (Figure 1). Again note that some, or all, of the major neuromodulator systems in the forebrain known to be influenced by music - β-endorphin, oxytocin, and dopamine – have the potential to be involved.

Several studies have argued that the therapeutic effects of music are not merely due to distraction (Roy et al., 2008; Lu et al., 2019, 2023). Furthermore, music still reduces outcome measurements of pain even when the music is delivered during general anesthesia and therefore cannot be attributed to distractive influence (Nilsson et al., 2003; Simcock et al., 2008; Hole et al., 2015; Kühlmann et al., 2018). On the other hand, Lunde et al. (2022) reported that the analgesic effect of 5 min of (not self-chosen) music in healthy subjects was not blocked by opioid or dopamine antagonists, but the effectiveness of music was predicted by an individual’s expectation that they would obtain pain relief. Others have reported that positive expectancy is less effective than music in decreasing pain sensitivity (Hsieh et al., 2014). The lack of effect of the dopamine antagonist (Lunde et al., 2022) may be due to the type and mode of presentation of the music excerpt given the known role of dopamine in the anticipation and rewarding experience of familiar music (Pereira et al., 2011; Salimpoor et al., 2011; Zatorre and Salimpoor, 2013; Ferreri et al., 2019). Note also that the opioid antagonist naloxone blocked the synchronous dance induced increase in pain threshold although no change in social closeness was registered (Tarr et al., 2017). The likely role of oxytocin and its cognate receptor in communal music making and pain relief (Kenny and Faunce, 2004; Hopper et al., 2016; Weinstein et al., 2016; Harvey, 2020; Good and Russo, 2022) is yet to be examined. Related to these issues, some have found no change in ‘chills’ or subjective responses using opioid blockers when listening to music (Laeng et al., 2021; Mas-Herrero et al., 2023) while others reported a decrease in pleasure after naltrexone delivery (Mallik et al., 2017). Catastrophization and the negative prediction of pain is linked to altered activity in regions such as ACC, prefrontal cortex, cingulate and insula (Tu et al., 2019; Antioch et al., 2020; Koppel et al., 2023), and is associated with an increased nociceptive experience (e.g., Brazenor et al., 2022). Importantly, this type of negative mindset reduces the effectiveness of music-based therapies (Chai et al., 2020; Powers et al., 2022).

The complex web of interactive circuits that underpin the psychophysiological complexities of pain are now well-known, involving multiple regions in cortex, limbic pathways, thalamus, hypothalamus and specific regions in the midbrain and brainstem. An implication of previous sections of this review is that music may contribute to remedial plasticity in circuits and networks altered in the persistent pain experience. Here we discuss another possible mode of interaction between the perception of pain and the experience of music – neural oscillations or brain waves. These rhythmic patterns of synchronized neural activity flowing within and across, and linking, neighboring regions of the brain have different repetitive frequencies (delta, 1–4 Hz; theta, 4–8 Hz; alpha, 8–13 Hz; beta, 13–30 Hz, gamma, 30–120 Hz), each associated with different brain states. Interestingly, there is evidence that oscillatory brain activity is linked to pain perception (Ploner and Gross, 2019; Kenefati et al., 2023; Li et al., 2023b). Pain-induced changes in gamma oscillations in somatosensory cortex have been described (Gross et al., 2007), while noxious heat stimulation in healthy subjects was shown to increase gamma wave activity in bilateral mPFC but decrease alpha and beta wave activity in somatosensory cortex (Nickel et al., 2017). Specific patterns of altered brainwave activity involving theta, alpha and gamma oscillations have been recorded in prefrontal areas and anterior cingulate in people with chronic pain (Kenefati et al., 2023). Supporting a link between gamma oscillations and pain perception, variability in amplitude of these oscillations was found to predict inter-individual pain sensitivity (Hu and Iannetti, 2019) and others have reported links between reduced pain perception and modulated delta, beta or gamma band oscillations (Hauck et al., 2013).

Different frequencies of sound vibration can affect a wide range of neurological and physiological functions, gamma waves (around 40 Hz) having significant effects on various levels of neural plasticity (reviewed in Bartel and Mosabbir, 2021). Music is of course made up of a vast array of sound frequencies and has been shown to have measurable effects on oscillatory activity (Thaut et al., 2005; Fujioka et al., 2015; Kučikienė and Praninskienė, 2018; Yurgil et al., 2020; Lerousseau et al., 2021; Yang et al., 2022; Nandi et al., 2023). Interestingly then, in subjects listening to preferred music, EEG recordings revealed reduced low frequency oscillations associated with lower ratings of pain (Lu et al., 2019), and Gu et al. (2020) reported that, compared to happy or neutral music, sad music was the most effective in alleviating pain, associated with altered brain oscillations in beta and gamma bands. Perhaps linking these studies, the autobiographical recall of sad music results in activation of gamma but also alpha bands (Gupta et al., 2023).

Evidence presented so far demonstrates the capacity of music to reduce the perception of pain via a number of neuromodulators that are directly involved in modifying ascending nociceptive transmission, at levels ranging from peripheral dorsal root ganglia to cerebral cortex. But music can also regulate other functions such as breathing, relaxation and autonomic nervous system activity, changes typical of altered attentional and conscious states associated with mindfulness and meditation. fMRI and PET studies have compared patterns of brain activation and deactivation associated with mindfulness and different types of meditation (Tang et al., 2015; Fox et al., 2016). Mindfulness meditation was associated with altered activity in the ACC, PFC, insula, striatum (caudate and putamen) and amygdala. In the Fox et al. (2016) review, some differences were seen with different types of practice, but several brain regions showed consistent changes, including the insula, pre/supplementary motor cortices, dorsal ACC and OFC. Overlay of these regions with many of those involved in music processing is evident (Figure 1) and the effects of mindfulness on pain relief appear to be distinct from non-specific effects (Zeidan et al., 2012, 2015; Adler-Neal et al., 2020; Tan and Kuner, 2021).

Reduced pain intensity ratings during mindfulness meditation were associated with increased activity in ACC and anterior insula, while reduced unpleasantness ratings were accompanied by increased activity in OFC and reduced thalamic activity (Zeidan et al., 2011). Others have reported reduced pain-related activity in somatosensory cortex (Nakata et al., 2014). A recent review on the impact of meditation on acute pain also described the involvement of these locations, but included activity changes (some up, some down) in subcortical PAG and RVM (Wipplinger et al., 2023). Importantly, the effectiveness of meditation in reducing acute and chronic pain intensity and unpleasantness varies depending on the experience of the individual (Nakata et al., 2014; Jinich-Diamant et al., 2020). A systematic review of mindfulness-based stress reduction (MBSR) compared to cognitive behavioral therapy (CBT) suggested MBSR could be applied within CBT or in addition to CBT for reducing pain severity, pain interference and psychological distress in chronic pain (Khoo et al., 2019). Other music therapy-based programs involving, for example, cooperative music composition and interaction (Metzner et al., 2022), or a combination of exercise and musical agency (Fritz et al., 2018; Schneider et al., 2022), have also been reported to lessen anxiety and decrease the experience of chronic pain.

As with music-based therapies (Metzner et al., 2022), there is evidence that mindfulness/meditation can enhance parasympathetic activity and HRV (Adler-Neal et al., 2020), but there is an important difference because pain relief is not blocked by opioid antagonists (Zeidan et al., 2016). Indeed, naloxone administration during meditation was shown to enhance pain relief, perhaps by unmasking a non-opioid pathway (May et al., 2018; see also Case et al., 2021). The alternative involvement of GABAergic and dopaminergic systems has been suggested, but there is also now some evidence for increased levels of salivary oxytocin when using mindfulness to reduce anxiety and improve mood (Bellosta-Batalla et al., 2020; Good and Russo, 2022). From the perspective of pain relief and anxiolysis, more research is needed here, especially given earlier studies reporting elevated oxytocin when listening to relaxing (Ooishi et al., 2017) or soothing (Nilsson, 2009) music.